Abstract 218: Ewing sarcoma gene, EWS, role in mitochondrial homeostasis

Abstract Peroxisome proliferator-activated receptor γ coactivator (PGC-1α) is a central regulator of mitochondria biogenesis, function and cellular energy metabolism. PGC-1α protein is intrinsically unstable but the mechanism by which PGC-1α stability is regulated is not well understood. Here, we report that a multifunctional protein EWS (Ewing sarcoma) is critical for PGC-1α protein stability and mitochondrial homeostasis. EWS inactivation results in a rapid degradation of PGC-1α via ubiquitin-dependent proteasome pathway and reduces mitochondrial abundance. Re-introduction of EWS in Ews-deficient cells restores PGC-1α expression and mitochondrial anomalies. In the absence of Ews, expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased and depletion of Fbxw7 in Ews-null cells restores PGC-1α expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice and expression of slow myosin heavy chain is significantly decreased in skeletal muscles of Ews-/- mice compared to controls. Furthermore, Ews-null mice display reduced expression of mitochondrial biogenesis, respiration and fatty acid β-oxidation genes in the liver and abnormally high serum lactate levels. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1α protein stability. Citation Format: Jun Hong Park. Ewing sarcoma gene, EWS, role in mitochondrial homeostasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 218.